The goal of this interagency agreement is to provide support of National Toxicology Program (NTP) hazard identification (or hazard assessment) activities targeted toward the prevention of diseases or adverse effects caused by environmental exposure to chemical or physical agents. These cooperative studies continue to improve the risk assessment process by determining quantitatively what constitutes an adverse health effect on the immune system in humans. These studies evaluate unique cohorts of individuals from professions associated with immune-mediated occupational diseases including asthma, respiratory and contact allergy, chronic beryllium disease, rhinitis, and silicosis. Occupational cohorts are being studied for a number of endpoints including, impact of genetic polymorphisms on inflammatory disease development and clinical outcomes, the role that genetic variations play in environmental and workplace related diseases and identification of unique immunological biomarkers for disease. A major emphasis has been placed on cytokine polymorphisms, especially within the MHC region, as a large number of occupational/environmental diseases are associated with chronic inflammatory responses and, thus, immune responses. A project which investigates the contribution of genetic variability in the immune-inflammatory-antioxidant responses to the development and/or severity of irritant contact dermatitis in health care workers continued in FY12. During this fiscal year the study completed recruitment of 300 additional subjects from the health care sector through collaboration with Department of Family Medicine at West Virginia University. Analysis of the patch test and questionnaire data obtained from113 healthcare workers showed that patch testing with low concentrations of sodium lauryl sulfate may predict future development of dermatitis. Genetic analyses have been completed using microarray platforms. In addition, nearly half of the study participants (140) were followed-up for interval and seasonal changes in their dermatitis status. The analysis of genetic and non-genetic data from this project has been initiated. A second project investigates the association between functional polymorphisms within immune/inflammatory and antioxidant genes and the occurrence and clinical outcomes of asthma caused by low and high molecular weight agents, and gene-gene/gene-environment interactions. This project is a collaboration with the Universities of Montreal and Cincinnati. During the FY12, 38 samples were received from subjects exposed to diisocyanates. Statistical analysis of genetic variations in MHC region has been completed. Genotyping of the single nucleotide polymorphisms in xenobiotic metabolizing and antioxidant enzyme genes (N-acetyltransferases, epoxide hydrolase 1 (EPHX1), glutathione S-transferases (GST), manganese superoxide dismutase (SOD2)) and monocyte chemotactic protein-1 gene have been completed. Analysis of antioxidant gene data showed an association between variations in EPHX1, GST and SOD2 genes and diisocyanate asthma. Subject recruitment, genotyping and data analysis for this project are ongoing. A third project investigates genetic profiles in individuals with allergic contact dermatitis, with a specific focus on nickel allergy. This study is in collaboration with Case Western Reserve University and DartmouthHitchcock Medical Center. The study population consists of nickel-sensitized patients, patients sensitized to weak allergens, and patients with reactions to more than 3 allergens (polysensitization). Comparisons will be made to non-sensitized subjects. All patients who are patch tested in the Contact Dermatitis Clinics at Case Western and Dartmouth will be invited to participate. Recruited patients will fill out questionnaires that detail demographic information and medical history, patch tests will be applied to assess the degree of skin reaction to the standard screening series of sensitizers and whole blood will be obtained for genetic studies. Subject recruitment and sample processing are ongoing. The Chronic Beryllium Disease project investigates the contribution of genetic variations in the MHC region to the development of beryllium sensitization and disease. Sample collection and processing have been completed, and genetic and statistical analyses are in progress. A final project examines the association between genetic variations in immune response genes and antibody response to childhood vaccinations (HBV, PCV7, DTaP). The analysis of genetic data related to major histocompatibility complex is ongoing.